The present invention relates to increasing enantioselectivity in reactions with borane reagents, and especially, to increasing enantioselectivity in the reduction of a prochiral substrate with a borane reagent and a chiral catalyst.
Borane reagents such as borane-tetrahydrofuran complex (sometimes referred to as THFB) are valuable reagents for the reduction of functional groups and for hydroboration reactions with carbon-carbon double and triple bonds. For example, functional groups reduced by borane-tetrahydrofuran complex include aldehyde, ketone, acyl chloride, lactone, epoxide, ester, amide, oxime, imine, and nitrile. Borane-tetrahydrofuran complex is a very selective and clean reducing agent. Because the borane is complexed to the low-boiling (65xc2x0 C.), common solvent, tetrahydrofuran, no byproduct residues are generated. Typically a reduction is quenched with excess methanol to deactivate any remaining borane-tetrahydrofuran complex and distilled to remove the boron from the desired products as the methylborate/methanol azeotrope.
The enantioselective reduction of prochiral ketones with borane-tetrahydrofuran complex in the presence of an oxazaborolidine chiral catalyst such as (R)-MeCBS (a methyl-substituted chiral oxazaborolidine named after Corey, Bakshi, and Shibata) is a very important tool for the synthesis of alcohols in high optical purity. See, for example, Corey, E. J. and Helel, C. J., xe2x80x9cReduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method,xe2x80x9d Angew. Chem. Int. Ed., 37, 1986-2012 (1998); U.S. Pat. No. 4,943,635; and Franot, C. et al., A Polymer-Bound Oxazaborolidine Catalysts: xe2x80x9cEnantioselective Borane Reductions of Ketones,xe2x80x9d Tetrahedron: Asymmetry, 6:11, 2755-2766 (1995).
However, the selectivity of the reaction has been found to be affected by a number of parameters including, for example, temperature and borane source/batch. In that regard, the enantioselectivity of (R)-MeCBS catalyzed reductions has been found to be quite low for various commercial samples of THFB. Several researchers have presumed that the widely variable results achieved with commercially available THFB were a result of decomposition thereof. See Jones, T. K. et al., xe2x80x9cAn Asymmetric Synthesis of MK-0417. Observations on Oxazaborolidine-Catalyzed Reductions,xe2x80x9d J. Org. Chem., 56, 763-769 (1991).
In that regard, although THFB is a very valuable reagent, THFB complexes are known to decompose during transportation and storage at ambient temperature and to thermally decompose during reaction. To prevent decomposition during transportation and storage, stabilizers are typically added to borane-tetrahydrofuran complex. Typically, a hydride source such as a metal hydride (for example, potassium hydride, sodium hydride or lithium hydride) or sodium borohydride (NaBH4) is added to THFB. Sodium borohydride and other hydrides have been shown to be quite effective in stabilizing THFB. At least one study has also shown that sodium borohydride leads to strongly enhanced activity in the reduction of ketones. Jockel, H. and Schmidt, R., xe2x80x9cKinetics of Direct Borane Reduction of Pinacolone in THF,xe2x80x9d J. Chem. Soc., Perkin Trans. 2, 2719-2723 (1997). Other borohydride sources include, for example, potassium borohydride, lithium borohydride, and tetraalkylammonium borohydride. Moreover, metal alkoxides (for example, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-amylate, potassium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide, sodium methoxide, potassium methoxide and lithium methoxide) can be added to generate a borohydride stabilizing agent within THFB.
It is very desirable to develop borane compositions and methods of reaction that improve enantioselectivity.
In one aspect, the present invention provides a method of increasing enantioselectivity in a reduction reaction of a prochiral substrate with a borane reagent including or containing a borohydride species (for example, a borohydride stabilized borane-tetrahydrofuran complex) catalyzed by a chiral catalyst. As used herein, the term xe2x80x9cborohydride speciesxe2x80x9d refers to compounds of boron and hydrogen and includes, for example, anionic borohydrides. The method includes generally the step of limiting the concentration of borohydride species in the borane reagent (for example, borane-tetrahydrofuran complex). In the case of borane-tetrahydrofuran complex, the method includes generally the step of maintaining the concentration of borohydride species in the borane-tetrahydrofuran complex below approximately 0.005 moles per mole of BH3 during the reduction of the prochiral substrate. More preferably, the concentration of borohydride species in the borane-tetrahydrofuran complex is below approximately 0.0015 moles per mole of BH3 during the reduction of the prochiral substrate. Most preferably, the concentration of borohydride speicies in the borane-tetrahydrofuran complex is below approximately 0.0005 moles per mole of BH3 during the reduction of the prochiral substrate. Prochiral substrates suitable for use in the present invention include, for example, ketones, imines and oximes.
As used herein and as used commonly in the chemical arts, the term xe2x80x9cketonexe2x80x9d refers generally to a compound having the formula: 
The term xe2x80x9ciminexe2x80x9d refers generally to a compound having the formula: 
The term xe2x80x9coximexe2x80x9d refers generally to a compound having the formula: 
In the above formulas, R and Rxe2x80x2 are preferably independently different, an alkyl group or an aryl group (Ar). Rxe2x80x3 is preferably H, xe2x80x94SiR3 or an alkyl group. Reductions of such prochiral substrates are discussed, for example, in Tilyer, R. D. et al., xe2x80x9cAsymmetric Reduction of Keto Oxime Ethers Using Oxazaborolidine Reagents. The Enantioselective Synthesis of Cyclic Amino Alcohols,xe2x80x9d Tetrahedron Letters, 36:25, 4337-4440 (1995); Cho, B. T. and Ryu, M. H., xe2x80x9cAsymmetric Borane Reduction of Ketoxime O-Trimethylsilyl Ethers Mediated by a Chiral 1,3,2-Oxazaborolidine Derived from (xe2x88x92)-Ephedrine,xe2x80x9d Bull. Korean Chem. Soc., 15:3, 191-192 (1994); and Shimizu, M. et al., xe2x80x9cStereocontrol in the Reduction of 1,2-Diimine with an Oxazaborolidine Catalyst. Highly Stereoselective Preparation of (R,R)-1,2-Diphenyl-ethylenediamine,xe2x80x9d Tetrahedron Letters, 36:47, 8607-8610 (1995).
Borane-tetrahydrofuran complex and other borane reagents may be prepared in a manner to maintain the concentration of borohydride species in the borane-tetrahydrofuran complex below a desired level (for example, below approximately 0.005 moles per mole of BH3 in the case of borane-tetrahydrofuran complex. For example, borane-tetrahydrofuran complex may be prepared by the addition of diborane to tetrahydrofuran with a known amount of a borohydride stabilizer. In that regard, a known amount of a borohydride stabilizer can be added. As used herein, the term xe2x80x9cborohydride stabilizerxe2x80x9d refers generally to borohydride compounds such as sodium borohydride and to compound(s) that generate a borohydride species within the borane-tetrahydrofuran complex. Alternatively, borane-tetrahydrofuran complex can be made without using a borohydride stabilizer. Preferably, borane-tetrahydrofuran complex is stored at or below 20xc2x0 C. before the reduction reaction to reduce decomposition.
Borane-tetrahydrofuran complex and other borane reagents may also be prepared with a concentration of borohydride species greater than a desired threshold concentration (for example 0.005 moles per mole of BH3 in the case of borane-tetrahydrofuran complex), and the concentration of borohydride species decreased before the reduction reaction. The concentration of borohydride species may, for example, be decreased by the addition of a Lewis acid. Example of a suitable Lewis acid include BF3, BF3 etherate complex (for example, BH3xe2x80x94THF), ZrCl4, AlCl3, FeCl3 or TiCl4.
In the case of borane-tetrahydrofuran complex, the concentration of borane-tetrahydrofuran complex per liter of tetrahydrofuran is preferably at least 1.0M. More preferably, the concentration of borane-tetrahydrofuran complex per liter of tetrahydrofuran is at least 1.5M. Most preferably, the concentration of borane-tetrahydrofuran complex per liter of tetrahydrofuran is at least 2.0M.
Preferably, the prochiral substrate is added to a mixture of borane reagent (for example, borane-tetrahydrofuran complex) and chiral catalyst. The case that the prochiral substrate is a ketone and the chiral catalyst is a chiral oxazaborolidine is an example of a reduction reaction of the present method.
In another aspect, the present invention provides a method of increasing enantioselectivity in a reduction reaction of a prochiral substrate with a borane reagent including a borohydride species that is catalyzed by a chiral catalyst. The method includes the step of reducing the detrimental effect the borohydride species has on enantioselectivity by adding a Lewis acid. Borane reagents suitable for use in the present invention include, but are not limited to, borohydride stabilized borane-tetrahydrofuran complex, as well as dimethylsulfide borane (DMSB) or diethylanilineborane (DEANB) when, for example, prepared from sodium borohydride. As discussed above, suitable Lewis acids include, but are not limited to, BF3, BF3 etherate complex, ZrCl4, AlCl3, FeCl3 or TiCl4. Preferably, the Lewis acid is BF3 or BF3 etherate complex.
In the case that a borohydride stabilized borane-tetrahydrofuran complex is used, the concentration of borane-tetrahydrofuran complex per liter of tetrahydrofuran is preferably at least 1.0M. More preferably, the concentration of borane-tetrahydrofuran complex per liter of tetrahydrofuran is at least 1.5M. Most preferably, the concentration of borane-tetrahydrofuran complex per liter of tetrahydrofuran is at least 2.0M. The borane-tetrahydrofuran complex is preferably stored at a temperature at or below approximately 20xc2x0 C. prior to reaction. Likewise, the prochiral substrate is preferably added to a mixture of borane-tetrahydrofuran complex and chiral catalyst.